Clopidogrel is administrated as its hydrogensulfate (syn. Bisulfate) salt. Its antiplatelet activity makes it an effective drug for reducing ischemic strokes, heart attacks and in atherosclerosis (a vascular disease causing claudication). Atherosclerosis is a buildup of plaque in the walls of arteries, which leads to thickening, and the reduction in the elasticity of the arteries. High Cholesterol, high blood pressure, smoking and infection also causes an injury to the inner walls of the arteries, which leads to the atherosclerosis. The plaque formation leads to blood clotting which is due to the platelet aggregation at the site of the injury. This clotting becomes an obstacle for the flow of the blood to the vital organs causing heart attacks or other severe problems.
Antiplatelet activity which fights against Atherosclerosis is exhibited by Clopidogrel, which binds adenosine diphosphate to its receptor and thereby induces platelet reduction, which is desirable in fighting against atherosclerosis. Clopidogrel has found to be more effective in inhibiting platelet aggregation than aspirin and is also mild towards gastrointestinal tract. (S) enantiomer of clopidogrel is pharmaceutically active and is administrated as bisulfate salt.
U.S. Pat. No. 4,529,596, discloses a racemic mixture of clopidogrel bisulfate and process for preparation of such mixture, which involves condensation reaction between methyl-2-chloro-o-chlorophenylacetate and 4,5,6,7-tetrahydro thieno[3,2-c]pyridine. The reaction produces racemic clopidogrel.
U.S. Pat. No. 4,847,265 discloses process for preparation of the dextro-rotatory enantiomer of the clopidogrel bisulfate. Racemic clopidogrel is resolved using camphor sulfonic acid to obtain optically pure dextro rotatory isomer. The patent describes the crystallization of the (S) enantiomer using dimethylformamide, ketones and alcohols. Amongst ketones, acetone is used for crystallization.
U.S.Pat. No. 5,036,156, discloses a method for preparation of an intermediate in the synthesis of clopidogrel, 2-chloro- αbromophenyl acetic acid and a process for condensing methyl ester with tetrahydrothienopyridine. The patent also describes process for preparation of pyridine derivative, which is one of the intermediate for preparation of clopidogrel.
U.S. Pat. No. 6,080,875 describes a process for preparation of methyl (+)-(S)-a-(2-thienyl-2-ethylamino)-a-(2-chlorophenyl)acetate hydrochloride by reaction of sodium-2-thienylglycidate with (S) 2-chloro phenyl glycine in presence of cyanoborohydride. This intermediate is further used to prepare (S) clopidogrel. The patent also describes the process for recemization of phenyl glycine esters.
U.S. Pat. No. 6,180,793 describes a process for preparation of (S) clopidogrel by reaction of 2-thiophene ethanol with (S)-2- chlorophenyl glycineamide, (S)-2-chlorophenyl-α-amino acetonirile or (S)-2-chlorophenyl glycine methyl ester. The resulting compound is cyclised, hydrolysed and esterified.
U.S. Pat. No. 5,204,469 discloses enantioselective process for preparation of clopidogrel through the reaction of (+)-2-chlorophenyl glycine and an activated form of 2-thiophene ethanol followed by cyclization with formaldehyde.
U.S. Pat. No. 6,800,759 describes a process for resolution of racemic clopidogrel, along with the conversion of (R) enantiomer of the clopidogrel to (S). The (S) enatiomer is separated by crystallizing it as camphor sulfonate salt from hydrocarbon, or a mixture of hydrocarbon and a co-solvent, preferably DMF:Toluene. The (R) enantiomer is then racemized and recycled by reaction with catalytic amount of base. The bases used are metal alkoxide, preferably potassium-t-butoxide.
U.S. Pat. No. 4,847,265 describes the formation of the dextrorotatory isomer of clopidogrel by salt formation using racemic compound and an optically active acid such as 10-L-camphorsulfonic acid in acetone, followed by successive recrystallisation until a product with constant rotatory power was obtained, followed by the release of the dextro rotatory isomer from its salt by a base. The hydrogen sulfate salt is then obtained by dissolution of the base in acetone cooled in ice and addition of concentrated sulphuric acid to precipitation. The precipitate thus obtained is crystalline Form I.
WO 98/39286 discloses racemization process for phenyl glycine ester in which a mixture of enantiomer of phenyl glycine ester is treated with a carbonyl compound in presence of carboxylic acid and single enantiomer of an N-protected-a-amino acid as a resolving agent. The formation of the imino intermediate causes the racemisation of the starting product and the precipitation of the single diastereomeric salt. After hydrolysis of the salt, an enantiomer of phenyl glycine ester is obtained.
WO/04/074215 discloses racemization process of (R) clopidogrel which involve conversion of (R) isomer to its racemic salt such as Hydrochloride, which is formed by dissolution of (R) Clopidogrel in Isopropyl alcohol and concentrated HCl. The salt thus formed is further converted to Racemic Clopidogrel base by treatment with base.
WO2004013147 describes a process for racemization of (R) isomer of the clopidogrel by the reaction with catalytic amount of the base preferably with potassium t-butoxide.
U.S. Pat. No. 6,429,210 describe process for preparation of the dextrorotatory S enantiomer of Clopidogrel bisulfate in the crystalline Form, Form II.
US2003114479 describes the novel crystalline forms, Form III, IV and V of clopidogrel hydrogen sulphate and amorphous form of clopidogrel hydrogen sulphate and processes for preparation of these forms and amorphous form as well as their pharmaceutical compositions. In this patent, polymorphic Form I is prepared by suspending amorphous clopidogrel hydrogen sulphate in ether.
International Patent application WO2004020443 describes process for preparation of Clopidogrel bisulfate Form I, which comprises separating out crystalline Form I from the solution of clopidogrel in the form of free base or salt in a solvent selected from the series of the primary, secondary or tertiary C1-C5 alcohols or their Esters with C1-C4 carboxylic acids or optionally of mixtures thereof.
International application WO 2004048385 describes a process for the preparation of crystalline Form I of S-Clopidogrel hydrogen sulphate by reacting the optically active base, (S)-(+) clopidogrel with concentrated sulfuric acid, wherein the salt formed by the said reaction in the reaction medium is precipitated with the precipitating solvent such as aliphatic or cyclic ethers and/or their mixture or isobutyl methyl ketone.
Form II of Clopidogrel Bisulfate is thermodynamically more stable and hence small change in condition during the preparation of Form I can result in Form II.
The present invention relates to the novel process for resolution of racemic clopidogrel base followed by conversion of the resolved (S) isomer to crystalline Clopidogrel bisulfate Form I. The present invention also relates to the racemization of unwanted (R) isomer. The present invention also relates to a process for resolution of clopidogrel base which is simple and less time consuming. The present invention also relates to the process for preparation of crystalline Form I of Clopidogrel Bisulfate from (S) clopidogrel base, which is reproducible. The present invention also relates to the process for preparation of crystalline Form I of Clopidogrel Bisulfate, which is cost effective and economical. The present invention also relates to the process for preparation of crystalline Form I of Clopidogrel Bisulfate, which is commercially viable.